High performance liquid chromatographic analysis and preclinical pharmacokinetics of the heteroarotinoid antitumor agent, SHetA2

Zhang, Yilong; Hua, Yousheng; Benbrook, Doris M.; Covey, Joseph M.; Dai, Guowei; Liu, Zhongfa; Chan, Kenneth K.

doi:10.1007/s00280-006-0211-z

Cited by 27 publications

(35 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The efficacy, toxicity, pharmacokinetics and formulation of SHetA2 are currently being evaluated in the National Cancer Institute's (NCI's) Rapid Access to Intervention Development (RAID) program (Application 196, Compound NSC 726189). The RAID pharmacokinetic studies demonstrated that micromolar concentrations of SHetA2 can be achieved and maintained in mice [35] indicating that concentrations sufficient to differentially induce apoptosis in cancer cells over normal cells can be targeted in clinical trials.…”

Section: Discussionmentioning

confidence: 98%

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

et al. 2005

Self Cite

View full text Add to dashboard Cite

The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute's human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists.

show abstract

Section: Discussionmentioning

confidence: 98%

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…The efficacy, toxicity, pharmacokinetics, and formulation of SHetA2 were evaluated in the National Cancer Institute's Rapid Access to Intervention Development (RAID) program (Application 196, Compound NSC 726189) and now in the Rapid Access to Preventive Intervention Development (RAPID) program. The RAID pharmacokinetic studies showed that micromolar concentrations of SHetA2 can be achieved in mice (19), indicating that concentrations sufficient to differentially induce apoptosis in cancer cells over normal cells can be targeted in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Liu

Hannafon

Gill

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Flex-Het drugs induce apoptosis in multiple types of cancer cells, with little effect on normal cells. This apoptosis occurs through the intrinsic mitochondrial pathway accompanied by generation of reactive oxygen species (ROS). The objective of this study was to determine if direct or indirect targeting of mitochondria is responsible for the differential sensitivities of cancer and normal cells to Flex-Hets. Mitochondrial effects and apoptosis were measured using JC-1 and Annexin V-FITC dyes with flow cytometry. Bcl-2, Bcl-x L , and Bax were measured by Western blot. Flex-Hets induced mitochondrial swelling and apoptosis in ovarian cancer cell lines but had minimal to no effects in a variety of normal cell cultures, including human ovarian surface epithelium. Effects on inner mitochondrial membrane (IMM) potential were variable and did not occur in normal cells. Two different antioxidants, administered at concentrations shown to quench intracellular and mitochondrial ROS, did not alter Flex-Het -induced mitochondrial swelling, loss of IMM potential, or apoptosis. Inhibition of protein synthesis with cycloheximide also did not prevent FlexHet mitochondrial or apoptosis effects. Bcl-2 and Bcl-x L levels were decreased in an ovarian cancer cell line but increased in a normal culture, whereas Bax expression was unaffected by Flex-Hets treatment. In conclusion, ROS seems to be a consequence rather than a cause of mitochondrial swelling. The differential induction of apoptosis in cancer versus normal cells by Flex-Hets involves direct targeting of mitochondria associated with alterations in the balance of Bcl-2 proteins. This mechanism does not require IMM potential, ROS generation, or protein synthesis.

show abstract

“…This in vitro study however, suffers from the same limitations as the clinical studies in the rarity of uterine cancer cell lines and patients with MMT and sarcoma histologies. SHetA2 decreased the survival of all three cell lines at physiologically achievable concentrations [16], but did not enhance their sensitivities to the chemotherapeutic agents. Similar to the differential effect of SHetA2 previously observed in ovarian cancer cell lines in comparison to normal and benign cultures [10,13], two of the three uterine cancer cell lines were more sensitive to SHetA2 in comparison to normal endometrial cells.…”

Section: Resultsmentioning

confidence: 99%

Sensitivities of Uterine Adenocarcinoma, Mixed Mullerian Tumor (MMT) and Sarcoma Cell Lines to Chemotherapeutic Agents and a Flex-Het Drug

Hyde

Benbrook²

2006

American J. of Pharmacology and Toxicology

Self Cite

View full text Add to dashboard Cite

The administration and combination of a variety of chemotherapeutic agents for treatment of advanced or recurrent uterine cancer of different histologies is under current debate. Mixed Mullerian Tumors (MMTs), which contain both adenocarcinoma and sarcoma components, are the most rate histologic type and it is therefore difficult to conduct clinical trials to determine if they should be treated like endometrial adenocarinomas or like sarcomas. Flexible Heteroarotionoids (Flex-Hets) are a promising class of anti-cancer drugs with low toxicity that have demonstrated activity against a wide variety of cancer types, but their efficacy in uterine cancers is unknown. The objective of this study was to determine if cell lines established from endometrial carcinoma (HEC-1-A), uterine sarcoma (SK-UT-1) and MMT (MES-SA) cancers exhibit differential sensitivities to cisplatin, carboplatin, paclitaxel, docetaxel, doxorubicin and SHetA2, if SHetA2 can enhance sensitivity to the chemotherapeutic drugs and if SHetA2 exhibits a differential effect on uterine cancer cells in comparison to normal endometrial cells using a cytotoxicity assay. These cell lines did not differ in their sensitivities to platinum or taxel drugs. Doxorubicin was active against the sarcoma but not the adenocarcinoma or MMT cell lines. SHetA2 decreased the survival of all three cell lines, but did not enhance their sensitivities to the chemotherapeutic agents. Two of the three uterine cancer cell lines were more sensitive to SHetA2 in comparison to normal endometrial cells. In conclusion, doxorubicin appears to have a greater effect against sarcoma than other uterine histology types. SHetA2 is affective against uterine cancer cell lines, but does not enhance their sensitivities to chemotherapeutic agents.

show abstract

High performance liquid chromatographic analysis and preclinical pharmacokinetics of the heteroarotinoid antitumor agent, SHetA2

Abstract: A highly sensitive HPLC/UV method for the quantification of SHetA2 in plasma has been developed to support pharmacokinetics of SHetA2 in the mouse. Pharmacokinetic behaviors of this drug appear to be favorable for future development.

Cited by 27 publications

References 10 publications

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria

Sensitivities of Uterine Adenocarcinoma, Mixed Mullerian Tumor (MMT) and Sarcoma Cell Lines to Chemotherapeutic Agents and a Flex-Het Drug

Contact Info

Product

Resources

About